PROJECT SUMMARY/ABSTRACT This proposal details a five-year translational research training program for mentored career development in molecular profiling, exercise physiology and trial conduct. The candidate is a recently appointed Cardiology faculty member at Beth Israel Deaconess Medical Center and the outlined proposal builds on the candidate?s background in cardiovascular prevention and exercise physiology to provide three new domains of expertise ? metabolomics, genetics, and exercise clinical trials. The applicant?s development will occur through a blend of laboratory training, didactic courses, and scientific conferences. The candidate?s mentor is a recognized leader in molecular profiling, exercise science, and cardiometabolic disease. The additional mentorship team has a distinguished mentoring record and vast expertise in metabolomics, genetics and exercise science. We recently identified a novel plasma metabolite, Dimethylguanidino valeric acid (DMGV) that is a very early marker of cardiometabolic disease and participant in a biochemical pathway (AGXT2) relevant to exercise responsiveness and cardiovascular disease. In recently published human data, we found that DMGV levels decreased after 20 weeks of aerobic exercise training (ET), however individuals with higher baseline levels of DMGV demonstrated attenuated improvements in lipid traits and insulin sensitivity after completing ET. The applicant now seeks to extend these studies by relating DMGV levels, and additional AGXT2 pathway intermediates (e.g. BAIBA, ADMA, glycine) to exercise-induced cardiovascular (e.g. maximal oxygen uptake [VO2max] and blood pressure) adaptations (Aim 1). Further, the applicant will apply unbiased metabolomics techniques to identify novel biochemical pathways related to exercise responsiveness (Aim 2). Finally, the applicant will identify genetic determinants of relevant metabolites identified in Aim 2 by interrogating large, population-based cohorts with existing genetics and metabolomics data, and integrate findings with long-term health outcomes to identify novel biochemical pathways involved in exercise and cardiometabolic health (Aim 3). In parallel, the applicant will integrate the same metabolomics techniques with cardiac MRI data in subjects with metabolic syndrome in order to characterize subclinical cardiac dysfunction, and design an exercise clinical trial in this population (Aim 4) as part of an R01-level award and transition to independence. Regular exercise leads to improvements in cardiometabolic health, however significant inter-individual differences exist and, further, the molecular underpinnings of regular exercise?s salutary effects remain poorly defined. This proposal will provide the applicant with the required training and expertise in molecular profiling, exercise physiology, and clinical trials in order to study chronic exercise adaptation in healthy subjects. Ultimately, this work will lay the foundation for future investigation into the clinical and molecular responses to regular exercise in patients with overt cardiometabolic disease (e.g. metabolic syndrome) at high risk for heart failure as part of applicant?s transition to research independence.